Long-term smoking is the leading preventable cause of cancers and of premature mortality. This is the revised competing continuation of a genetic epidemiologic collaboration among investigators in the U.S., Australia and Finland, to identify genes that influence risks for heavy smoking and nicotine dependence. We have obtained interview data and blood samples from 1200 affected sib pairs concordant for heavy smoking, and their tobacco-exposed siblings, recruited through the Australian and Finnish twin panels. QTL linkage analyses using 10cM microsatellite marker genome scan data have identified a strong linkage signal in both Australian and Finnish subsamples for our primary heaviness-of-smoking (HoS) phenotype, on Chr 22 (combined single-point LOD 5.2, genome-wide significance, p=0.003). This competing continuation seeks to identify the gene or genes on Chr 22 which are contributing to HoS using the efficiency of existing data and large informative samples with complimentary strengths. This will be achieved by (i) genotyping SNPs at 1cM density, in existing genome scan families, to better define our linkage peak; (ii) conducting a genetic association study, with high-throughput genotyping of 1500 SNPs within our primary linkage region in 1000 unrelated Finnish male heavy smokers (ATBC chemoprevention trial participants who smoked 40+ cigarettes per day) and 1000 Finnish male population controls (Health2000 participants), and in 1000 unrelated Australians with a history of regular, heavy cigarette smoking, 1000 Australian tobacco-exposed controls, and 1,000 Australian controls with a history of regular but low cigarette consumption (50% women in each Australian series); (iii) replication of genetic associations thus identified in a second panel of 2000 ATBC male heavy smokers and an additional 2,000 male population controls, or in Australian large sibship families (for Australian specific findings); (iv) genotyping additional SNPs for genes having SNPs associated with HoS, to identify haplotypes showing the strongest association for HoS, and sequencing high and low risk haplotypes to attempt to identify functional SNPs; and (v) characterizing the contributions to smoking behavior and correlated psychiatric and other substance use disorders of any genes thus identified, using the Finnish and Australian families already recruited, and additional Australian large sibship families that form a general community sample.